8bbh | pdb_00008bbh
The crystal structure of a mouse Fab fragment TL1 in complex with a human Glucose-6-phosphate isomerase peptide 293-307
Structural highlights
DiseaseG6PI_HUMAN Defects in GPI are the cause of hemolytic anemia non-spherocytic due to glucose phosphate isomerase deficiency (HA-GPID) [MIM:613470. It is a form of anemia in which there is no abnormal hemoglobin or spherocytosis. It is caused by glucose phosphate isomerase deficiency. Severe GPI deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment. FunctionG6PI_HUMAN Besides it's role as a glycolytic enzyme, mammalian GPI can function as a tumor-secreted cytokine and an angiogenic factor (AMF) that stimulates endothelial cell motility. GPI is also a neurotrophic factor (Neuroleukin) for spinal and sensory neurons.[1] [2] [3] Publication Abstract from PubMedOBJECTIVES: To identify the arthritogenic B cell epitopes of glucose-6-phosphate isomerase (GPI) and their association with rheumatoid arthritis (RA). METHODS: IgG response towards a library of GPI peptides in patients with early RA, pre-symptomatic individuals and population controls, as well as in mice, were tested by bead-based multiplex immunoassays and ELISA. Monoclonal IgG were generated, and the binding specificity and affinity were determined by ELISA, gel size exclusion chromatography, surface plasma resonance and X-ray crystallography. Arthritogenicity was investigated by passive transfer experiments. Antigen-specific B cells were identified by peptide tetramer staining. RESULTS: Peptide GPI(293-307) was the dominant B cell epitope in K/BxN and GPI-immunised mice. We could detect B cells and low levels of IgM antibodies binding the GPI(293-307) epitopes, and high affinity anti-GPI(293-307) IgG antibodies already 7 days after GPI immunisation, immediately before arthritis onset. Transfer of anti-GPI(293-307) IgG antibodies induced arthritis in mice. Moreover, anti-GPI(293-307) IgG antibodies were more frequent in individuals prior to RA onset (19%) than in controls (7.5%). GPI(293-307)-specific antibodies were associated with radiographic joint damage. Crystal structures of the Fab-peptide complex revealed that this epitope is not exposed in native GPI but requires conformational change of the protein in inflamed joint for effective recognition by anti-GPI(293-307) antibodies. CONCLUSIONS: We have identified the major pathogenic B cell epitope of the RA-associated autoantigen GPI, at position 293-307, exposed only on structurally modified GPI on the cartilage surface. B cells to this neo-epitope escape tolerance and could potentially play a role in the pathogenesis of RA. Pathogenic antibody response to glucose-6-phosphate isomerase targets a modified epitope uniquely exposed on joint cartilage.,Li T, Ge C, Kramer A, Sareila O, Leu Agelii M, Johansson L, Forslind K, Lonnblom E, Yang M, Xu B, Li Q, Cheng L, Bergstrom G, Fernandez G, Kastbom A, Rantapaa-Dahlqvist S, Gjertsson I, Holmdahl R Ann Rheum Dis. 2023 Jun;82(6):799-808. doi: 10.1136/ard-2022-223633. Epub 2023 , Mar 1. PMID:36858822[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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